Organ transplantation is a therapeutic tool for the treatment of severe organ failure, yet transplant rejection remains a major cause of the graft loss. In addition to organ rejection, ischemia/reperfusion injury (IRI) often accompanies organ transplantation. See, e.g., Lutz, et al., J. Inflamm. (Lond), 7:27 (2010). IRI has an influence on not only early post-transplant graft dysfunction, but also the long-term poorer outcomes of a transplanted organ. Moreover, IRI, which has been implicated in heart attack, stroke, traumatic head injury, and during cardiac surgery, is a major burden on individuals and health care systems worldwide. See, e.g., Arumugam, et al., Shock, 32:4-16 (2009). For example, ischemic cardiac injury following acute myocardial infarction (AMI) is the leading cause of heart failure and mortality in the United States. See, Heidenreich, et al., Circulation, 123:933-944 (2011).
Ischemic myocardial injury occurs in many clinical conditions, such as heart transplantation, cardiac bypass, AMI, and coronary stenting after AMI. See, e.g., Bopassa, Am. J. Cardiovas. Dis., 2:223-236 (2012). The restoration of myocardial perfusion, known as reperfusion, saves the ischemic myocardium, but also can induce a deleterious effect in addition to that of ischemic stress. Subsequent restoration of blood flow in ischemic tissues is often followed by reperfusion injury, which results in increased organ injury. In the case of AMI, occlusion of the coronary artery decreases the delivery of oxygen and of nutrients to segments of the myocardium. Timely treatment of AMI, using angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for left ventricular systolic dysfunction (LVSD), aspirin or fibrinolytic to dissolve blood clots, or percutaneous coronary intervention (PCI) to open blockages, has greatly decreased 30-day in-hospital deaths. See e.g., Van de Werf, et al., Eur. Heart J., 29″2909-2945 (2008). However, even with successful blood-flow restoration, IRI often results in tissue damage and adverse remodeling. The rate of developing post-AMI heart failure increases while acute mortality decreases. Similarly, acute kidney IRI is a common and important problem in both native and transplanted kidneys, contributing to both early and late dysfunction of the organs. See, e.g, Kosieradzki and Rowinski, Transplant Proc., 40:3279-3288 (2008).
IRI is a series of events in which one event triggers the next. See, e.g., Chan, et al., Br. J. Surg., 90:1470-1478 (2003). Thus “ischemic cascade” is actually a misnomer, since events are not always linear: in some cases they are circular, and sometimes one event can cause or be caused by multiple events. In addition, cells receiving different amounts of blood may go through different chemical processes. A growing body of literature suggests that both innate and adaptive immune responses play crucial roles in regulating the inflammation and the subsequent wound healing response. See, e.g., Epelman and Mann, J. Cardiovas. Transl. Res., 5(6):827-3 (2012). The IRI cascade usually goes on for two to three hours, but can last for days, even after normal blood flow returns. There are still no specific treatments for IRI insults. Thus, there is a need for therapeutic agents that can be used in patients to can protect organs against IRI and against organ transplant rejection.